rs397508295
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.174_177del(p.Asp58GlufsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
CFTR
NM_000492.4 frameshift
NM_000492.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.71
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-117509040-GGATA-G is Pathogenic according to our data. Variant chr7-117509040-GGATA-G is described in ClinVar as [Pathogenic]. Clinvar id is 53373.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117509040-GGATA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.174_177del | p.Asp58GlufsTer32 | frameshift_variant | 3/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.174_177del | p.Asp58GlufsTer32 | frameshift_variant | 3/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2016 | The c.174_177delTAGA pathogenic mutation, located in coding exon 3 of the CFTR gene, results from a deletion of 4 nucleotides at nucleotide positions 174 to 177, causing a translational frameshift with a predicted alternate stop codon (p.D58Efs*32). This mutation was reported in a patient diagnosed with cystic fibrosis secondary to meconium ileus at birth, who was heterozygous for a second pathogenic mutation (Clavel C et al. Hum. Mutat., 1997;9:368-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Aug 22, 2017 | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 23, 2018 | Variant summary: CFTR c.174_177delTAGA (p.Asp58GlufsX32) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.178G>T (p.Glu60X), c.223C>T (p.Arg75X), c.262_263delTT (p.Leu88fsX22)). The variant was absent in 245558 control chromosomes. The c.174_177delTAGA variant has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Strateva 2009, Kilinc 2002, De Wachter 2017, Clavel 1997), indicating that it is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 18, 2022 | - - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at